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Leukemia. 2018 May;32(5):1211-1221. doi: 10.1038/s41375-018-0025-0. Epub 2018 Jan 30.

The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function.

Author information

1
Innere Medizin II, Hämatologie und Onkologie, Universitätsklinikum Jena, Jena, Germany.
2
Leibniz Institute on Aging, Fritz-Lipmann Institute, Jena, Germany.
3
Department of Hematology and Oncology, Otto-von-Guericke University Medical Center, Magdeburg, Germany.
4
Department of Cardiology, Otto-von-Guericke University Medical Center, Magdeburg, Germany.
5
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany.
6
Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
7
Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.
8
III Medical Department, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
9
Medical Clinic for Hematology, Oncology and Tumor Biology, Charite University Hospital, Berlin, Germany.
10
Innere Medizin II, Hämatologie und Onkologie, Universitätsklinikum Jena, Jena, Germany. florian.heidel@med.uni-jena.de.
11
Leibniz Institute on Aging, Fritz-Lipmann Institute, Jena, Germany. florian.heidel@med.uni-jena.de.

Abstract

Cell fate determinants influence self-renewal potential of hematopoietic stem cells. Scribble and Llgl1 belong to the Scribble polarity complex and reveal tumor-suppressor function in drosophila. In hematopoietic cells, genetic inactivation of Llgl1 leads to expansion of the stem cell pool and increases self-renewal capacity without conferring malignant transformation. Here we show that genetic inactivation of its putative complex partner Scribble results in functional impairment of hematopoietic stem cells (HSC) over serial transplantation and during stress. Although loss of Scribble deregulates transcriptional downstream effectors involved in stem cell proliferation, cell signaling, and cell motility, these effectors do not overlap with transcriptional targets of Llgl1. Binding partner analysis of Scribble in hematopoietic cells using affinity purification followed by mass spectometry confirms its role in cell signaling and motility but not for binding to polarity modules described in drosophila. Finally, requirement of Scribble for self-renewal capacity also affects leukemia stem cell function. Thus, Scribble is a regulator of adult HSCs, essential for maintenance of HSCs during phases of cell stress.

PMID:
29467485
DOI:
10.1038/s41375-018-0025-0
[Indexed for MEDLINE]

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